Molecular genetic mechanisms responsible for the development and progression of prostate cancer remain largely unknown. Identification of sites of frequent and recurring allelic deletion or gain is a first step toward identifying some of the important genes involved in the malignant process. Previous studies in retinoblastoma (Friend, et al Nature, 323:643-6 (1986)) and other cancers (Cawthon, et al., Cell, 62:193-201 (1990); Baker, et al., Science, 244:217-21 (1989); Shuin, et al., Cancer Res, 54:2832-5 (1994)) have amply demonstrated that definition of regional chromosomal deletions occurring in the genomes of human tumors can serve as useful diagnostic markers for disease and are an important initial step towards identification of critical genes. Similarly, regions of common chromosomal gain have been associated with amplification of specific genes (Visakorpi, et al., Nature Genetics, 9:401-6 (1995)). Additionally, definition of the full spectrum of common allelic changes in prostate cancer may lead to the association of specific changes with clinical outcome, as indicated by recent studies in colon cancer and Wilms'tumor (Jen, et al., N. Engl. J. Med., 331:213-21 (1994); Grundy, et al., Cancer Res, 54:2331-3 (1994)).
Prostate cancer allelotyping studies (Carter, et al., Proc Natl Acad Sci USA, 87:8751-5 (1990); Kunimi, et al., Genomics, 11:530-6 (1991)) designed to investigate one or two loci on many chromosomal arms have revealed frequent loss of heterozygosity (LOH) on chromosomes 8p (50%), 10p (55%), 10q (30%), 16q (31-60%) and 18q (17-43%). Recently, several groups have performed more detailed deletion mapping studies in some of these regions. On 8p, the high frequency of allelic loss has been confirmed, and the regions of common deletion have been narrowed (Bova, et al., Cancer Res, 53:3869-73 (1993); MacGrogan, et al., Genes Chromosom Cancer, 10:151-159 (1994); Bergerheim, et al., Genes Chromosom Cancer, 3:215-20 (1991); Chang, et al., Am T Pathol, 144:1-6 (1994); Trapman, et al., Cancer Res, 54:6061-4 (1994); Suzuki, et al., Genes Chromosom Cancer, 13:168-74 (1995)). Similar efforts also served to narrow the region of common deletion on chromosome 16q (Bergerheim, et al., Genes Chromosom Cancer, 3:215-20 (1991); Cher, et al., J Urol, 153:249-54 (1995)). Other prostate cancer allelotyping studies utilizing a smaller number of polymorphic markers have not revealed new areas of interest (Phillips, et al., Br J Urol, 73:390-5 (1994); Sake, et al., Cancer Res, 54:3273-7 (1994); Latil, et al., Genes Chromosom Cancer, 11:119-25 (1994); Massenkeil, et al., Anticancer Res, 14:2785-90 (1994)). At present, allelotyping studies are limited by the low number of loci studied, low case numbers, heterogeneous groups of patients, the use of tumors of low or unclear purity, and lack of standardization of experimental techniques. For these reasons, it has been difficult to compare frequencies of alterations between studies, and we have yet to gain an overall view of regional chromosomal alterations occurring in this disease.
Comparative genomic hybridization (CGH) is a relatively new molecular technique used to screen DNA from tumors for regional chromosomal alterations (Kallioniemi, et al., Science, 258:818-21 (1992) and WO 93/18186). Unlike microsatellite or Southern analysis allelotyping studies, which typically sample far less than 0.1% of the total genome, a significant advantage of CGH is that all chromosome arms are scanned for losses and gains. Moreover, because CGH does not rely on naturally occurring polymorphisms, all regions are informative, whereas polymorphism-based techniques are limited by homozygous (uninformative) alleles among a fraction of tumors studied at every locus.
CGH can detect and map single copy losses and gains in prostate cancer with a high degree of accuracy when compared with the standard techniques of allelotyping (Cher, et al., Genes Chromosom Cancer, 11:153-162 (1994)). Copy-number karyotype maps have been generated for prostate cancer showing several recurrently altered regions of the genome (Cher, et al., Genes Chromosom Cancer, 11:153-162 (1994); Visakorpi, et al., Cancer Res, 55:342-347 (1995)).
Although previous studies have begun to reveal a genome-wide view of chromosomal alterations occurring in primary and recurrent prostate cancer, metastatic prostate cancer has not been examined in depth. The present invention addresses these and other needs in the prior art.